The present invention relates to an advantageous process for the preparation of 3-acetoxy-2-methylbenzoyl chloride.
3-Acetoxy-2-methylbenzoyl chloride is an important precursor for the preparation of pharmaceutical active compounds. In particular, it can be used as a structural unit for novel highly active HIV protease inhibitors, which inhibit the biological activity of the HIV protease enzyme. As a result of the inhibition of the biological activity of the HIV protease enzyme, the replication of the HIV virus is suppressed. In this way, novel possibilities of treatment of the immunodeficiency disease AIDS result. The preparation of an active compound of this type, which in the end is a decahydroisoquinoline derivative, is described in WO 95/09843. As is evident from Example 82 of WO 95/09843, [3S-(3R*, 4aR*, 8aR*, 2'S*, 3'R*)]-2-[3'-amino-2'-hydroxy-4'-phenyl]butyl decahydroisoquinoline-3-N-t-butylcarboxamide is reacted with 3-acetoxy-2-methylbenzoic acid in the presence of a dehydrating agent. The reaction proceeds at room temperature over a period of time of 2 days and leads to the formation of an amide bond between the 3-acetoxy-2-methylbenzoic acid and the primary amino group of the abovementioned decahydroisoquinoline.
The disadvantage of this synthesis is the rather long reaction time, the use of a dehydrating agent as well as a yield of only 65%.
With respect to the preceding explanations, the object is to prepare a substance whose use leads to a simplification of the synthesis and which can also be prepared on an industrial scale with justifiable expenditure.
This object is achieved by a process for the preparation of 3-acetoxy-2-methylbenzoyl chloride ##STR1##
The abovementioned disadvantages can be avoided by reacting the abovementioned decahydroisoquinoline with 3-acetoxy-2-methylbenzoyl chloride. The good reactivity of 3-acetoxy-2-methylbenzoyl chloride advantageously results in a marked reduction of the reaction time. Moreover, the use of a dehydrating agent, such as the dicyclohexylcarbodiimide used in Example 82 of WO 95/09843, can be dispensed with entirely.
A further advantage is the high purity of the 3-acetoxy-2-methyl-benzoyl chloride, which can be purified in a simpler and better manner than 3-acetoxy-2-methylbenzoic acid.
Whereas 3-acetoxy-2-methylbenzoic acid can only be purified by complicated recrystallization, 3-acetoxy-2-methylbenzoyl chloride can be purified with low expenditure by fractional distillation.
An additional advantage to be mentioned is that the product losses in a comparatively simple fractional distillation are lower than in a labor-intensive recrystallization.
As already mentioned previously, the present invention relates to a process for the preparation of 3-acetoxy-2-methylbenzoyl chloride.
WO 95/09843 describes a multistage process for the preparation of 3-acetoxy-2-methylbenzoic acid. This process starts from 3-methoxybenzoyl chloride. The 3-methoxybenzoyl chloride is reacted with aniline to give 3-methoxy-N-phenylbenzamide. In a second step, the 3-methoxy-N-phenylbenzamide is reacted with 2 equivalents of n-butyllithium and then alkylated using methyl iodide. 3-Methoxy-2-methyl-N-phenylbenzamide is formed here, which is then reacted with aqueous hydrochloric acid and aqueous hydrogen bromide in boiling acetic acid with hydrolysis of the amide group and cleavage of the methoxy group to give 3-hydroxy-2-methylbenzoic acid. The 3-hydroxy-2-methylbenzoic acid must be acylated with acetic anhydride in order to obtain the 3-acetoxy-2-methyl-benzoic acid. The individual reaction steps are described in greater detail in WO 95/09843 under Preparation 9 A, B and C and Example 81.
This synthesis route has several disadvantages. On the one hand, the reaction with n-butyllithium has to be carried out at rather low temperatures. As is evident from Preparation 9 B, the temperatures are in the range from -70 to -15.degree. C. Low temperatures of this type can only be achieved on an industrial scale with very high expenditure.
On the other hand, the use of lithium alkyls is generally not unproblematical and necessitates working cautiously and carefully with this very reactive class of substance. Handling on an industrial scale requires particular safety measures and additional expenditure on apparatus.
Furthermore, the use of aggressive substances such as hydrochloric; acid and hydrogen bromide leads to materials problems, since the reaction equipment has to be sufficiently resistant to corrosion by this substance. This can only be achieved by expensive materials.
Moreover, problems result in the disposal of waste gases and effluents polluted with hydrogen chloride and hydrogen bromide. Since neither hydrogen chloride nor hydrogen bromide must pass into the environment, they have to be specifically removed from the waste gases and effluents.